Bristol-Myers Melanoma Drug Unleashes Immune System

For more than three decades, scientists have dreamed of unleashing one of nature’s most powerful inventions, the human immune system, to treat cancer.

Now, a wave of treatments that activate the immune system to attack tumors is emerging from drug-company laboratories, giving hope of longer life to patients with terminal lung cancer, leukemia, brain tumors and melanoma, Bloomberg Businessweek reports in its May 31 edition.

Leading the push is Bristol-Myers Squibb Co.’s experimental drug for skin cancer, one of dozens of immunotherapies to be spotlighted next week at the American Society of Clinical Oncology meeting. In its late stages, melanoma can be lethal within months, killing more than 65,000 people a year. Bristol-Myers’s drug, called ipilimumab, extended life in its deadly final phase, three small trials have found. If those results stand in data reported at the meeting, the drug may get U.S. regulatory approval as early as next year and may be in doctors’ hands in 2012, the company said in March 4 investor call.

“We have hundreds of patients who are still alive after taking this treatment, and that is something unheard of” in advanced-stage melanoma, Renzo Canetta, Bristol-Myers’s vice president of oncology clinical research, said in a telephone interview.

Earlier Trials

In the earlier trials, ipilimumab kept more than one-third of patients alive for at least 18 months, about a year longer than existing treatments for terminal melanoma. The trial to be reported at the cancer meeting tested the drug in 676 patients for five years, according to the study’s description.

Bristol-Myers, based in New York, rose 62 cents, or 2.7 percent, to $23.34 at 4 p.m. in New York Stock Exchange composite trading. The company gained 20 percent in the past 12 months.

Melanoma affects about 130,000 people a year according to the World Health Organization. No new treatment has been approved for the disease in more than a decade and current medicines keep patients with the advanced stage of the disease alive for six to eight months, said Steven O’Day, who tested the drug for Bristol-Myers at the Angeles Clinic and Research Institute in Santa Monica, California.

Ipilimumab is central to Bristol-Myers’s plan to bolster its share of the $52 billion cancer-drug market and counter generic competition during the next six years to drugs with more than $11 billion in annual sales. If approved, the drug may have $1 billion in annual sales within five years, said Linda Bannister a health-care analyst at Edward Jones & Co.

Successful Strategy

Success with ipilimumab will be a sign as to whether the company’s strategy of acquiring small biotechnology companies -- they bought the drug’s creator Medarex Inc. for $2.4 billion last year -- is paying off.

“Bristol faces a large amount of patent expirations and from that perspective ipilimumab is very important, this could be big for them,” said Bannister, who is based in Des Peres, Missouri. A success “will show that Bristol made a really good acquisition with Medarex,” she said.

Jedd Wolchok, a skin cancer researcher at Memorial Sloan-Kettering Cancer Center in New York, is a believer.

One of the first patients Wolchok treated with the drug in 2004 was a 24-year-old woman who likely had less than a year to live after failing on other treatments. After getting four doses intravenously, her tumors shrunk and eventually disappeared. She has started a family since and sends Wolchok a Christmas card yearly, he said.

‘Resetting the Balance’

“We are resetting the balance between the person and the tumor and the tumor no longer has the upper hand,” Wolchok said in a telephone interview. “We have been talking about turning cancer into a chronic disease, and this shows it is possible.”

Bristol-Myers’s drug is derived from mice that were genetically altered to create a human version of an antibody, a soldier in the immune system army. The antibody is designed “to push the accelerator down” on the system, said O’Day.

The drug blocks a protein called CTLA-4, which when working properly keeps the immune system from getting too revved up and attacking the body’s own tissue. Tweaked by scientists at Medarex, the medicine opens the way for the body to release excessive white-blood cells that attack the tumors the way they would another foreign invader, such as a virus.

Along with showing signs of aiding skin cancer patients, the drug’s action may also work against tumors of the lung and prostate, said Trevor Polischuk, an analyst with OrbiMed Advisors LLC in New York.

‘A Game Changer’

“This could be a game changer in cancer,” Polischuk said in a telephone interview.

While ipilimumab is now one of Bristol-Myers’s most promising drugs in development, it could have died in testing two years ago had researchers not noticed a strange phenomenon among patients who they thought weren’t benefiting.

A study released in December 2007 showed that it failed to meet the U.S. Food and Drug Administration’s criteria of benefiting at least 10 percent of melanoma patients. In 2008, when Bristol-Myers had been expecting to file for approval with the FDA, the company said it would delay its application after the agency said the current studies weren’t enough to garner approval.

Company researchers, though, kept studying the drug on a hunch it was having a benefit that wasn’t detected in the studies. They noticed an odd trend among some patients whose tumors continued to get larger while they were on the medicine. Once these patients were removed from the study because they weren’t showing a benefit, their tumors unexpectedly began to shrink and the researchers found they were living months and, in some cases, years longer than expected.

Inflammatory Response

Bristol-Myers realized that what appeared to be tumor progression was an inflammatory response from the treatment as the white blood cells called T-cells attacked the tumor.

If researchers hadn’t excluded these patients from the data reported to the FDA in 2008, they may have been able to prove the benefit was greater than seen in previous studies, Bristol Myers’s Canetta said.

Ipilimumab won’t be the first in the latest family of cancer immunotherapies to show strong success against a cancer. Dendreon’s prostate cancer vaccine Provenge was cleared by the FDA on April 29. That day, Dendreon’s stock rose as much as 38 percent, and the Nasdaq Biotech Index had its biggest rise in six months.

Provoke, Redirect, Accelerate

Next week, at the American Society of Clinical Oncology meeting, the world’s biggest gathering of cancer doctors, a range of companies will show how their medicines will provoke, redirect, or accelerate the immune system to kill cancer cells. For instance, New York-based Pfizer Inc., the world’s biggest drugmaker, will present data on a brain tumor vaccine from a study that’s in the second stage of three needed for U.S. regulatory approval.

Micromet Inc., a Bethesda, Maryland, biotechnology company, will update doctors about a technology it developed that activates T-cells to attack tumors. German drugmaker Merck KGaA and Oxford BioMedica Plc of the U.K. will show how their vaccines work against breast and kidney malignancies.

The concept of immunotherapy has taken a long time to bear fruit. In the early 1970s, scientists started developing lab-grown proteins called monoclonal antibodies, designed either to block tumor growth or make tumors visible to other immune-system cells. They do this by homing in on specific molecules or “targets” on the surface of cancer cells.

Rituxan Launch

The first success came in 1997, when Genentech Inc. and Biogen Idec Inc. launched Rituxan, a drug for non-Hodgkin’s lymphoma that last year had $5.7 billion in revenue.

While these drugs are a big business for companies, most have shortcomings as medicines because they only targeted one of multiple growth drivers pushing the tumors, said Steven Rosenberg, chief of surgery at the National Cancer Institute in Bethesda, Maryland. “We need to do better than prolonging survival by months,” Rosenberg said.

Drugs like ipilimumab may be more effective for longer periods of time because they are training the immune system to recognize and attack cancer cells, researchers say.

“The hope is that we aren’t just extending, but that we are really curing people with widespread cancer,” said O’Day, the researcher in California “It is a little early to say that, but there is hope.”

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